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CRISPR enzyme protects bacteria by transforming infected cells into themselves

CRISPR enzyme protects bacteria by transforming infected cells into themselves

In the genome editing technology known as CRISPR-Cas9, RNA (blue) forms a complex with Cas9 protein (uneven structure). Cas9 unwinds target DNA (red) and acts as a molecular scalpel, cutting both chains. Cas13, a related protein, RNA slots instead of DNA. Credit: HHMI BioInteractive, CRISPR-Cas 9 Mechanism and applications

What does not kill the bacteria makes it stronger.

The enzyme that bacteria use to fight the virus acts not only on the virus, but also on the bacterium itself. It sends the bacteria to idle state and makes it a non-digestible virus propagation site. This protects the bacteria from mutated viruses passing alongside other immunological defense, the researchers report on May 29, 2019 in the journal the nature.

Disarming or killing host cells is a common strategy for the immune system, but the new work is the first to demonstrate the bacterial defense of CRISPR, says molecular biologist Luciano Marraffini, a researcher at the Medical Institute, Hovard Hughes, at Rockefeller University.

The Cas13 enzyme was discovered in 2015 and is part of a family of proteins that include Cas9, an enzyme best known for its role in gene regulation. In a popular tool, CRISPR, for example, scientists have used Cas9 to insert or modify specific genes. In nature, Cas proteins are a key part of the bacterial immune system. They disable viruses that infect bacteria by removing a DNA or RNA attacker.

The scientists already knew Cas13 was a bit strange in his family. If Cas9 is scalpel, Cas13 is more like a machete. Cutting takes place at specific, targeted locations, but also reduces the target. And unlike most Cas protein, it cuts RNA, not DNA.

"Cas13 has already become a very powerful diagnostic tool," says co-author Alekander Meeske, also in Rockefeller. Researchers can use it to quickly identify the virus in the blood of patients, even those who are present at very low levels. "What we did not know," he says, "is how Cas13's behavior affects bacterial immunity."

CRISPR enzyme protects bacteria by transforming infected cells into themselves

When viruses attack bacteria, as shown in this illustration, bacteria fight. Enzyme Cas13 protects bacteria against viruses that can avoid other immune responses. Credit: / Design Cells

Now, he and his colleagues have discovered that Cas13's seemingly random snacks are a valuable tool for bacterial defense. While most Cas enzymes protect bacteria by preventing the reproduction of viruses, Cas13 disables the bacterial host itself.

This is important because viruses can easily avoid CRISPR systems – only one genetic mutation in the region that Cas enzymes can do with a virus invisible to the immune system. Researchers have shown that Cas13 can catch those potentially "virtuoso" viruses.

First, Meeske and his colleagues analyzed how Cas13 affects RNA. The enzyme was largely cut by RNA, they discovered, breaking the RNA produced by the virus and the host cell. Even when Cas13 cut off RNA regions that were completely available for the virus, viruses still could not be reproduced. This suggested that the host cell somehow turned off the reproduction of the virus.

When Meeske then constructed mutated viruses that Cas13 could not recognize, viruses flourished within the Listeria bacterium. But by adding normal, non-mutated viruses together with mutated viruses, the cells were actually protected from infection – they switched Cas13 and cut off all of the RNA in the cell, he says. "It was so intuitive and surprising!"

Without RNA, bacterial cells could not continue to grow and function. In dysfunctional cells, the mutant virus could not be duplicated.

It is unclear whether the cells can return from this standstill or will eventually die, Meeske says. But by preventing viruses from multiplying, these cells protect the greater bacterial population from the threat.

The new CRISPR tool targets RNA in mammalian cells

More information:
Alekander J. Meeske et al. Cas13-induced cellular restraining prevents the growth of bacteria-resistant resistant to CRISPR, the nature (2019). DOI: 10.1038 / s41586-019-1257-5

Medical Institute Hovard Hughes

CRISPR enzyme protects bacteria by transforming infected cells into itself (2019, May 30)
taken on May 30, 2019
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